A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene.

PURPOSE: We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause. METHODS: Exome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed. RESULTS: We identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes. CONCLUSION: We describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.

A case of ciliary body mesectodermal leiomyoma with rapid growth and loss of vision necessitating enucleation.

INTRODUCTION: Mesectodermal leiomyoma of the ciliary body is a benign rare tumor that rarely presents acutely with a complicated clinical course. PRESENTATION OF CASE: We are reporting a 39-year-old healthy female who presented with subacute blurred vision in her right eye secondary to a ciliary body mass. Initial fine needle aspiration biopsy ruled out a melanoma but the patient meanwhile experienced rapid complicated growth of the mass with vision loss, for which her right globe was eventually enucleated. The tumor was diagnosed histopathologically to be mesectodermal leiomyoma. DISCUSSION: The clinical course of our case was unique because of the subacute onset of her symptoms, the rapid growth of her benign tumor, and the complicated tumor behaviour leading to enucleation. An acute presentation of mesectodermal leiomyoma has been reported only once among similar cases in the recent literature. The tumor in our case showed the characteristic histopathological and immunohistochemical findings described before. CONCLUSION: Ophthalmologists should be aware of the unusual acute/subacute presentation of a rather benign lesion. Delayed diagnosis may result in ophthalmic complications and loss of the globe.

Clinical, radiological and histopathological characteristics of surgically removed orbital hematic cysts: A case series.

BACKGROUND: Hematic cyst is a rare orbital condition that has a wide range of clinical presentation and is characterized pathologically by lack of endothelial lining. PURPOSE: To correlate clinical and radiological features of hematic cysts, to tissue diagnosis, and investigate the possible etiology behind this condition, its relation to trauma and other interesting histopathological findings. METHODS: Retrospective case series at King Khaled Eye Specialist Hospital (KKESH) and King Abdulaziz University Hospital (KAUH) of all orbital lesions with tissue findings supporting the clinical and/or radiological diagnosis of hematic cyst. RESULTS: A series of 13 cases was studied, 8 males and 5 females. Age ranged from 2 to 84 years with a median of 54. Most cases presented with proptosis (76.9%) and limitation of eye movements (69.2%). History of trauma was confirmed in only 2/13. The clinical diagnosis of hematic cyst was made prior to surgery in 38.4%. Magnetic Resonance Imaging (MRI) confirmed the presence of blood in the orbit in 7/7. Surgical intervention was the mainstay of treatment. Histopathologically, these lesions demonstrated variable constituents including blood break-down products (hemosiderin), macrophages, mononuclear inflammatory cells, hemorrhage, absent endothelial lining, reactive fibrosis and capsule-like formation. Cholesterol clefts with typical granulomas and multinucleated giant cells were present in 2 cases. A clue to an underlying vascular lesion was found histopathologically in 30.8%. None of the patients developed recurrence or long-term complications with an average follow up period of 1 year. CONCLUSION: Hematic cyst is a challenging clinical diagnosis that can be aided by radiological examination and histopathological confirmation. Trauma does not seem to play a major role while presence of a pre-existing vascular lesion with spontaneous hemorrhage may be an etiologic factor. Associated cholesterol granuloma is an interesting controversial finding. Surgical intervention is curative with possible persisting motility disturbance and/or the eye deviation and worse prognosis in post-traumatic cases.